Asymmetric Allylic Amination of Morita-Baylis-Hillman Adducts with Simple Aromatic Amines by Nucleophilic Amine Catalysis

Article abstract of DOI:10.1055/s-0037-1611740

Asymmetric allylic amination of Morita-Baylis-Hillman (MBH) adducts with simple aromatic amines is successfully realized by nucleophilic amine catalysis. A range of substituted α-methylene-β-arylamino esters is accessed in moderate to high yields (up to 8

Full text of DOI:10.1055/s-0037-1611740

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
A
en
S. Zhao et al.
Letter
Synlett
Asymmetric Allylic Amination of Morita–Baylis–Hillman Adducts
with Simple Aromatic Amines by Nucleophilic Amine Catalysis
O
SiMe3
Shuai Zhao
R1
R2
(DHQD)2AQN
(20 mol%)
Zhi-Li Chen
Xue Rui
OBoc
NH
OTf
N
R1NH2
+
+
CO2Me
N
CO2Me
R2
CO2Me
CaF2
p-xylene
72 h
KF
Ming-Mei Gao
Xin Chen*
18-crown-6
CH3CN
rt
rt
27 examples
up to 88% yield
97% ee
45% yield
90% ee
48% yield
91% ee
School of Pharmaceutical Engineering & Life Science,
Changzhou University, Changzhou, 213164, P. R. of China
xinchen@cczu.edu.cn
R1 = R2 = Ph
Received: 14.01.2019
Accepted after revision: 04.02.2019
Published online: 26.02.2019
In addition, asymmetric allylic aminations of racemic
MBH adducts mediated by nucleophilic Lewis bases have been
successfully developed with various N-nucleophiles includ-
ing indole, imines, enamines, imides, aliphatic amines and
pyrroles (Scheme 1b).7 However, the asymmetric allylic am-
ination of racemic MBH adducts using less-nucleophilic ar-
omatic amines mediated by Lewis bases still remains unde-
veloped.8 Considering the broad application of optically ac-
tive -alkylidene--amino carbonyl compounds, and our
interest in developing novel and practical asymmetric
transformations,9 we herein present an asymmetric allylic
amination of MBH carbonates with simple aromatic amines
by nucleophilic amine catalysis (Scheme 1c). Excellent en-
antioselectivities (up to 97% ee) were achieved for a wide
range of MBH carbonates and aromatic amines. In addition,
a pyrrole-2-carboxylate and a cyclic imide were also com-
patible with this catalytic system. A chiral multifunctional
tetrahydroquinoline derivative can be easily afforded from
the corresponding allylic amination product.
The initial study was undertaken with aniline (2a) and
MBH carbonate 3a in xylene at room temperature for 72
hours. A series of cinchona alkaloids and their derivatives
were screened as the nucleophilic amine catalysts (Figure 1),7
and the results are outlined in Table 1. Unmodified cincho-
na alkaloids 1a–d were found to be able to catalyze the al-
lylic amination reaction, giving the desired products in low
yields and with moderate ee values (Table 1, entries 1–4).
Among them, quinidine 1c gave the best results. Analogs of
1c with blocked hydroxy groups (1e,f) did not afford the de-
sired products (Table 1, entries 5 and 6). Hydrogenated ana-
logs 1g,h and -isocupreidine (-ICD) (1i) gave lower ee
values than 1c (Table 1, entries 7–9). Next, the cinchona al-
kaloid dimers 1j–l were tested as the catalysts (Table 1, en-
tries 10–12). To our delight, the allylic amination product
was obtained with 89% ee and in 52% yield when (DH-
QD)2AQN (1k) was used (Table 1, entry 11). Next, the effect
of the solvent on the reaction was carefully studied with
catalyst 1k (see the Supporting Information) and p-xylene
was found to be the best (Table 1, entry 13). To increase the
yield of the reaction, higher concentrations of the sub-
DOI: 10.1055/s-0037-1611740; Art ID: st-2019-l0023-l
Abstract Asymmetric allylic amination of Morita–Baylis–Hillman
(MBH) adducts with simple aromatic amines is successfully realized by
nucleophilic amine catalysis. A range of substituted -methylene--
arylamino esters is accessed in moderate to high yields (up to 88%) and
with excellent enantioselectivities (up to 97% ee). Inorganic fluorides
are found to be able to improve the enantioselectivity of the allylic ami-
nation reaction. A pyrrole-2-carboxylate and a cyclic imide are also
compatible with this catalytic system. A chiral 2,3-dihydroquinolin-4-
one derivative is easily obtained from the allylic amination product.
Key words MBH adducts, aromatic amines, asymmetric allylic amina-
tion, nucleophilic amine catalysis, inorganic fluorides
Optically active -alkylidene--amino carbonyl com-
pounds and their derivatives represent one type of highly
valuable synthons, which have broad applications in the
synthesis of complex natural products and medicinally rele-
vant molecules,1 and especially in the synthesis of chiral -
lactam derivatives.2 Traditional strategies to access these
building blocks include asymmetric aza-Morita–Baylis–
Hillman (MBH) reactions between electron-deficient ole-
fins and activated aldimines such as N-tosyl and N-mesyl
aldimines.3 However, aza-MBH reactions of electron-rich
aldimines, such as N-alkyl or N-aromatic imines, can be dif-
ficult to realize.4 In contrast, asymmetric allylic substitution
reactions of MBH carbonates5 with various N-nucleophiles
under catalysis by transition metal complexes1e,2a,2c,6 or or-
ganocatalysts7 is another straightforward strategy for the
synthesis of -alkylidene--amino carbonyl compounds.
Ding and co-workers have developed a palladium-catalyzed
asymmetric allylic amination of MBH carbonates with sim-
ple aromatic amines.2a,6d Both enantiomers of optically ac-
tive -methylene--arylamino esters were afforded with
excellent regio- and enantioselectivities by using aromatic
spiroketal-based bisphosphine ligands (Scheme 1a). Ezeti-
mibe was also easily accessed from the corresponding allyl-
ic amination product.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

B
S. Zhao et al.
Letter
Synlett
strates were applied in this catalytic system. When the con-
centration of 2a was increased from 0.05 M to 0.1 M, the
yield of the reaction was greatly improved, whereas the ee
value was almost unchanged (Table 1, entry 14). A de-
creased ee value was observed when the concentration of
the substrates was further increased to 0.2 M, although the
yield was improved as expected (Table 1, entry 15). Subse-
quently, several additives were investigated. When pyridine
was used, a sharp decrease in the yield and ee were ob-
served (Table 1, entry 16). Inorganic fluorides, especially
a) Ding's work: Pd-catalyzed asymmetric allylic amination of MBH carbonates with
simple aromatic amines
R1
R2
NH
[{Pd(allyl)Cl}2]
CO2Et
OAc
(R,R,R)-SKP ligand
NH2
CO2Et
R1
R2
+
[Pd2(dba)3]
NH
CO2Et
(S,S,S)-SKP ligand
R1 = R2 = H
b) Previous work: Lewis base catalyzed asymmetric allylic amination of MBH carbonates with different N-nucleophiles
LG
O
O
Nu-N
*
chiral Lewis base
R2
R2
Nu-NH
Nu-NH
+
R1
R1
O
O
Ph
Ph
NHAc
=
NH
R
R
NH
O
R1
N
NH
R
H
O
O
Ts
CO2R
R
Ts
R
O
N
N
R
H
N
N
H
H
H
c) This work: Lewis base catalyzed asymmetric allylic amination of MBH carbonates with simple aromatic amines
OBoc
NHAr
chiral Lewis base
CO2Me
ArNH2
+
CO2Me
R2
R2
· less-nucleophilic aromatic amines
· simple operation, readily available catalyst
· versatile products
Scheme 1 Asymmetric allylic substitution of MBH adducts
OMe
R
R
OMe
OBz
OAc
OH
OH
N
N
N
N
N
N
N
N
1a R = MeO
1b R = H
1c R = MeO
1d R = H
1e
1f
OMe
OH
N
N
OMe
N
N
N
O
OH
O
O
OH
N
N
N
OMe
MeO
N
N
N
N
1g
1h
1i
1j
N
N
N
N
O
O
O
O
OMe
MeO
OMe
N
N
MeO
O
O
N
N
N
N
1k
1l
Figure 1 The chiral nucleophilic amine catalysts screened
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

C
S. Zhao et al.
Letter
Synlett
CaF2, were found to be effective in improving the ee values
of the reaction (Table 1, entries 19–22).10 Thus, the opti-
mized conditions for the asymmetric allylic amination are
as follows: 1k (20 mol%) in p-xylene (0.1 M) with 5 equiva-
lents of CaF2 at room temperature for 72 hours (Table 1, entry
19).
products in moderate to high yields (up to 88%) and with
excellent enantioselectivities (up to 97% ee). The position
and electronic properties of the substituents on the aro-
matic ring of MBH carbonates 3 had little influence on the
enantioselectivity (4ab–an). When ortho-substituted sub-
strates were used, decreased yields were observed, proba-
bly due to steric hindrance (4ab, 4ah, 4ak). Comparable re-
sults were obtained when the phenyl ring of MBH carbon-
ate 3 was replaced with naphthyl (4ao) and thienyl (4ap)
substituents.
Table 1 Optimization of the Reaction Parameters
OBoc
NH2
1 (20 mol%)
We next investigated the scope of the aromatic amine
(Scheme 2). The presence of substituents on the aniline 2
had a slight influence on the enantioselectivity of the prod-
ucts 4ba–bi. However, decreased yields were observed
when anilines bearing m-Me (4bb), p-Me (4bc), o-F (4bd)
or p-Cl (4bg) substituents were used. This might be due to
the lower reactivities of these anilines, with studies show-
ing that significant amounts of the substrates were still
present in the reaction mixtures after 72 hours under the
optimized conditions. When the aniline was replaced with
2-naphthylamine, the desired product 4bj was obtained in
high yield and with excellent enantioselectivity. It was
noteworthy that product 4bk, a key synthetic intermediate
en route to the drug ezetimibe, could also be obtained in
moderate yield and with high enantioselectivity.2a,12
The absolute configurations of products 4 were deter-
mined by comparing the optical rotation value of 4aa
{[]D28 = –91.1 (c 0.7, CHCl3)} with those reported in the lit-
erature {[]D20 = –175.2 (c 1.0, CHCl3) for R-4aa in reference
2c}.2a,2c,6c Thus products 4 were assigned the R configura-
tion.
Based on experimental observations and literature re-
ports,7h,13 a plausible transition state is proposed in Figure
2. Michael addition to the vinylic moiety of the MBH car-
bonate by nucleophilic amine 1k gave the intermediate,
which would be probably formed as the E isomer and stabi-
lized by - stacking between the quinoline moiety and the
phenyl ring of the MBH carbonate. As the si face of the com-
plex is effectively blocked by the left half of the quinoline
moiety, the N-nucleophile would presumably approach the
re face in the preferable SN2′/anti-elimination manner to
give the final product.
NH
CO2Me
+
CO2Me
72 h
rt
2a
3a
4a
Entrya
1
Solvent
Additive
Yield (%)b
ee (%)c
1
1a
1b
1c
1d
1e
1f
xylene
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Pyf
15
14
27
24
trace
trace
65
23
64
13
52
28
56
78
81
56
75
74
80
79
78
80
61
47
74
5
2
xylene
3
xylene
4
xylene
5
xylene
ND
ND
61
68
43
17
89
52
90
89
87
44
81
81
92
91
90
91
6
xylene
7
1g
1h
1i
xylene
8
xylene
9
xylene
10
11
12
13
14d
15e
16d
17d
18d
19d
20d
21d
22d
1j
xylene
1k
1l
xylene
xylene
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
f
CaCl2
f
MgCl2
f
CaF2
f
MgF2
f
SrF2
f
BaF2
a Unless otherwise noted, the reaction was carried out with 2a (0.05 mmol),
3a (0.1 mmol), and 1 (0.01 mmol) in 1 mL of solvent at room temperature.
b Yield of isolated product.
MeO
N-nucleophile
MeO
N
c Determined by HPLC. ND = not determined
re face attack
d The reaction was carried out in 0.5 mL of p-xylene.
e The reaction was carried out with 2a (0.1 mmol), 3a (0.2 mmol), and 1k
(0.02 mmol) in 0.5 mL of p-xylene at room temperature.
f 500 mol% of additive was used.
N
H
H
CO2Me
N
N
O
O
O
O
With optimized reaction conditions in hand, we next
examined the substrate scope of the asymmetric allylic am-
ination reaction.11 As shown in Scheme 2, a variety of sub-
stituted MBH carbonates and aromatic amines were well
tolerated using this catalytic system, providing the desired
Figure 2 A plausible transition state model in the asymmetric allylic
amination reactions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

D
S. Zhao et al.
Letter
Synlett
R1
R2
OBoc
NH
1k (20 mol%)
R1NH2
+
CO2Me
CO2Me
R2
CaF2
p-xylene
72 h
4
rt
2
3
NH
NH
NH
NH
NH
NH
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
F3C
F
4aa, 80% yield, 92% ee
4ab, 50% yield, 89% ee
4ac, 77% yield, 90% ee
4ad, 48% yield, 96% ee
4ae, 85% yield, 95% ee
4af, 88% yield, 92% ee
NH
NH
NH
NH
NH
NH
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
F
Cl
Cl
4aj, 70% yield, 96% ee
Br
Cl
Br
4ag, 78% yield, 95% ee
4ah, 53% yield, 93% ee
4ai, 85% yield, 92% ee
4ak, 60% yield, 95% ee
4al, 77% yield, 92% ee
NH
NH
NH
NH
NH
NH
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
S
O2N
Br
4am, 66% yield, 97% ee
4an, 83% yield, 97% ee
4ao, 72% yield, 96% ee
4ap, 82% yield, 89% ee
4ba, 65% yield, 91% ee
4bb, 40% yield, 92% ee
F
F
Cl
Br
F
NH
NH
NH
NH
NH
NH
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
4bc, 49% yield, 88% ee
4bd, 31% yield, 93% ee
4be, 65% yield, 88% ee
4bf, 73% yield, 90% ee
4bg, 49% yield, 90% ee
4bh, 82% yield, 92% ee
F
OMe
NH
NH
CO2Me
NH
CO2Me
O
CO2Me
4bi, 75% yield, 91% ee
4bj, 83% yield, 91% ee
4bk, 45% yield, 93% ee
Scheme 2 Substrate scope of the asymmetric allylic amination reaction. Reaction conditions: 2 (0.05 mmol), 3 (0.1 mmol), 1k (0.01 mmol), p-xylene
(0.5 mL), CaF2 (0.25 mmol), room temperature, 72 hours. Yields of isolated products are reported. The ee values were determined by HPLC
To demonstrate the utility of the developed methodolo-
gy, asymmetric allylic amination reactions of MBH carbon-
ate 3a with other N-nucleophiles were conducted. To our
delight, methyl pyrrole-2-carboxylate and 1,8-naphthalim-
ide were well tolerated in this catalytic system. The desired
allylic amination products 4ca and 4da were afforded in
moderate yields and with higher enantioselectivities than
those reported in the literature (Scheme 3, eqs a and b).7d,7i
The chiral -methylene--arylamino ester 4aa is widely
recognized as a versatile synthetic intermediate.1 We found
that the allylic amination product 4aa reacted with the
aryne precursor 2-(trimethylsilyl)aryl triflate through a
cascade sequence involving an insertion/cyclization pro-
cess, as reported by He in 2016.1g Chiral 2,3-dihydroquino-
lin-4-one derivative 5a and insertion product 6a were pro-
duced with high enantioselectivities (Scheme 3, eq c).
In summary, we have described a highly efficient asym-
metric allylic amination reaction of MBH carbonates with
simple aromatic amines by employing a readily available
nucleophilic amine catalyst. A series of chiral -methylene-
-arylamino esters has been accessed in moderate to high
yields and with excellent enantioselectivities. Methyl pyr-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

E
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Letter
Synlett
OBoc
CO2Me
CO2Me
N
1k (20 mol%)
CO2Me
CO2Me
a)
b)
c)
N
+
CaF2
p-xylene
72 h
H
rt
4ca
50% yield
3a
84% ee
(73% ee in ref. 7d)
O
OBoc
1k (20 mol%)
CO2Me
NH
O
O
N
O
CaF2
p-xylene
72 h
+
CO2Me
rt
4da
71% yield
3a
91% ee
(90% ee in ref. 7i)
O
SiMe3
OTf
KF, 18-crown-6
NH
N
+
N
CO2Me
CO2Me
+
CH3CN
rt
5a
6a
4aa
92% ee
45% yield
91% ee
48% yield
91% ee
Scheme 3 (a) Asymmetric allylic amination of MBH carbonate 3a with methyl pyrrole-2-carboxylate. (b) Asymmetric allylic amination of MBH carbon-
ate 3a with 1,8-naphthalimide. (c) Synthesis of chiral 2,3-dihydroquinolin-4-one derivative 5a from allylic amination product 4aa and the aryne precur-
sor 2-(trimethylsilyl)aryl triflate
role-2-carboxylate and 1,8-naphthalimide were well toler-
ated in this catalytic system and gave the desired products
with improved enantioselectivities. In addition, a chiral 2,3-
dihydroquinolin-4-one derivative was obtained with re-
tained enantiopurity. We believe that the methodology pre-
sented herein is a good complement to the palladium-cata-
lyzed allylic amination reaction and might have applica-
tions in the synthesis of natural products and biologically
relevant compounds.
References and Notes
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Funding Information
We gratefully acknowledge the financial support from the National
Science Foundation of China (21602018, 21272029) and the Jiangsu
Overseas Visiting Scholar Program for University Prominent Young &
Middle-Aged Teachers and Presidents.
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n
a
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n
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i
n
a
(2
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2
0
1
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n
a
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c
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n
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e
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n
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ati
o
n
of
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n
a
(2
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0
2
9)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611740.
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orit
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(11) Asymmetric Allylic Amination; General ProcedureA solution
of amine 2 (0.05 mmol), MBH carbonate 3 (0.1 mmol), catalyst
1k (0.01 mmol) and CaF2 (0.25 mmol) in p-xylene (0.5 mL) was
stirred at room temperature for 72 hours. Then the reaction
mixture was directly purified by flash column chromatography
(eluting with EtOAc/petroleum ether, 10:1) to afford the
product 4.
Methyl (R)-2-[Phenyl(phenylamino)methyl]acrylate (4aa)
Colorless oil; 80% yield; 92% ee; []D28 = –91.1 (c 0.7, CHCl3). The
enantiomeric excess was determined by HPLC analysis with an
OD-H column (n-hexane/i-PrOH, 95:5), 1.0 mL/min,  = 254 nm,
tR (major) = 8.57 min, tR (minor) = 10.76 min. 1H NMR (300 MHz,
CDCl3):  = 7.40–7.28 (m, 5 H), 7.20–7.14 (m, 2 H), 6.75–6.70
(m, 1 H), 6.58 (dd, J = 8.4 Hz, J = 0.9 Hz, 2 H), 6.40 (s, 1 H), 5.97 (t,
J = 1.2 Hz, 1 H), 5.41 (s, 1 H), 4.16 (s, 1 H), 3.71 (s, 3 H); 13C NMR
(100 MHz, CDCl3):  = 166.8, 146.8, 140.7, 140.0, 129.3, 128.9,
128.0, 127.7, 126.4, 118.0, 113.5, 59.1, 52.1; HRMS (ESI): m/z [M
+ H]+ calcd for C17H18NO2: 268.1332; found: 268.1333.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F